A cancer is a malignant tumour of potentially unlimited growth. It is primarily the pathogenic replication (a loss of normal regulatory control) of various given types of cells found in the human body. By select mutation resulting from a primary lesion, the DNA of a cancer cell evolves and converts the cell into an autonomous system. Conventional cancer treatments have focused mainly on killing cancerous cells. Chemotherapeutic agents currently used for anti-cancer/anti-tumour therapy are selected for their toxicity towards rapidly proliferating cells. Most of them cause undesirable systemic effects such as cardiac or renal toxicity, marrow aplasia, alopecia, nausea and vomiting. During the last few years, many researchers have tried to eliminate these side effects by developing drugs having suitable physico-chemical properties allowing an increase of the availability of the drug to the tumour site. New molecules extracted from natural sources, synthetically or semi-synthetically produced, enzymes, radioisotopes, DNA toxins, various macromolecules, and antibodies against fibrin or against tumour-specific surface antigens are bound to drugs in an attempt to increase selectivity of the chemotherapeutic agents.
The effectiveness of most anticancer agents is greatly reduced because of their high toxicity and the nature of the illness. It is believed that the problem of high toxicity of the anticancer agents can be circumvented by chemical modifications of those structures in such a way that they act more specifically on tumour cells without increasing systemic toxicity. The research in this field is therefore mainly directed to the synthesis of anticancer agents which would possess high antineoplastic activity, low systemic toxicity and low mutagenicity on normal cells.
Heterocyclic compounds, especially heterocyclic azole derivatives, have been shown to have a wide spectrum of biological activities. One class of compounds with interesting biological activities is the imidazoles (derivatives containing a five-membered heterocyclic azole). A variety of biological activities have been reported for imidazole derivatives with different substitution patterns (Lee et al. Nature 1994 327:739-745; Abdel-Meguid el al. Biochemistry, 1994, 33:11671; Heerding et al. Bioorg. Med. Chem. Lett. 2001, 11:2061-2065; Bu et al. Tetrahedron Lett. 1996, 37:7331-7334; Lewis J R. Nat. Prod. Rep. 1999, 16:389-418; Lewis J R. Nat. Prod. Rep. 1998, 15:417-437 and 371-395).
Biological activities have also been reported for aryl-imidazole derivatives, for example, these compounds can act as modulators of multi-drug resistance in cancer cells (Zhang et al. Bioorg. Med. Chem. Lett. 2000, 10:2603-2605), inhibitors of p38 MAP kinase (Adams et al. Bioorg. Med. Chem. Lett. 2001, 11:867-2870, McLay et. al. Bioorg. Med. Chem. 2001, 9:537-554) and of cytokines (U.S. Pat. Nos. 5,656,644; 5,686,455; 5,916,891; 5,945,418; and 6,268,370), and inhibitors of bacterial growth (Antolini et al. Bioorg. Med. Chem. Lett. 1999, 9:1023-1028).
A few reports have indicated that triaryl-imidazole compounds can act as inhibitors of p38 MAP kinase (for example, see LoGrasso et al. Biochemistry, 1997, 36:10422-10427) and as modulators of multi-drug resistance in cancer cells (Sarshar et al. Bioorg. Med. Chem. Lett. 2000, 10:2599-2601), however, the majority of the literature indicates that these compounds have found use mainly as colour producing reagents (U.S. Pat. Nos. 4,089,747; 5,024,935; 5,047,318; 5,496,702; 5,514,550; and 5,693,589) and as photopolymerization initiators (U.S. Pat. Nos. 6,117,609 and 6,060,216), generally in dimeric form.
The potential anti-cancer activity of a number of compounds has been investigated by the National Cancer Institute (NCI), which has undertaken a large scale screening of several thousand compounds to try to identify those that have potential therapeutic application in the treatment of cancer (NCI Yeast Anticancer Drug Screen). The screen is based on the ability of candidate compounds to inhibit the growth of Saccharmyces cerevisiae strains that have mutations in genes related to cell cycle control and DNA repair damage. Compounds are initially screened against a panel of six yeast strains at a single concentration (Stage0). Compounds with activity in Stage0 are re-screened against the same panel at two concentrations (Stage1). Selected compounds with activity in Stage1 that also show selectivity are re-screened against a panel of 13 yeast strains at five concentrations (Stage2). Many of the results from the screening have been made available on the NCI/DTP website. The approach adopted in this screen is dependent on a candidate compound exerting its activity on certain cellular pathways (i.e. cell cycle control or DNA repair damage). The results generated by this type of screen, therefore, represent a very preliminary stage of screening for potential anti-cancer drugs and do not necessarily correlate with the ability of a compound to inhibit the growth of cancer cells in vitro or in vivo.
The NCI also provides an in vivo screening program to try to identify potential anti-cancer drugs (NCI In Vivo Anticancer Drug Screen). Many of the results from this screening program are also available from the NCI/DTP website.
Amongst those compounds tested in one or both of the NCI screens are some aryl imidazole compounds (NCI #322334, 338970, 144033). None of these three compounds showed any activity in the In Vivo Anticancer Drug Screen, even though one of these compounds (NCI #338970) had been reported as active in Stage0 testing in the Yeast Anticancer Drug Screen. The fact that this compound was active in the yeast screen yet showed no activity in the in vivo assay confirms that a positive result in the yeast screen is not necessarily predictive of the utility of a compound as in anti-cancer therapeutic.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.